Design of Elastic Networks with Evolutionary Optimized Long-Range Communication as Mechanical Models of Allosteric Proteins

Flechsig, Holger

doi:10.1016/j.bpj.2017.06.043

Cited by 56 publications

(73 citation statements)

References 51 publications

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“…Recent work associates the soft modes of protein conformations with the emergence of weakly connected regions as described above, but also 'cracks' [Miyashita et al 2003], 'shear bands' or 'channels' [Dutta et al 2018;Mitchell and Leibler 2017;Mitchell et al 2016;Rocks et al 2019;Tlusty 2016;Tlusty et al 2017] that enable low-energy viscoelastic motion [Joseph et al 2014;Qu and Zocchi 2013]. Such contiguous domains evolve in models of allosteric proteins [Flechsig 2017;Hemery and Rivoire 2015;Tlusty et al 2017].…”

Section: Biology As a Challenge To Theoristsmentioning

confidence: 99%

“…These inherent difficulties motivated the development of complementary approaches which utilized simplified coarse-grained models, such as lattice proteins [Lau and Dill 1989;Shakhnovich et al 1991] or elastic networks [Chennubhotla et al 2005]. Network and lattice models have been recently used to study the evolution of allostery in proteins and in biologically-inspired allosteric matter [Flechsig 2017;Hemery and Rivoire 2015;Rocks et al 2017;Tlusty 2016;Tlusty et al 2017;Yan et al 2017]. Our aim here is different: to construct a simplified condensed-matter model in terms of how the mechanical interactions within the protein shape its evolution.…”

Section: Mechanical Views On Protein Evolutionmentioning

confidence: 99%

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Colloquium: Proteins: The physics of amorphous evolving matter

2019

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Proteins are a matter of dual nature. As a physical object, a protein molecule is a folded chain of amino acids with multifarious biochemistry. But it is also an instantiation along an evolutionary trajectory determined by the function performed by the protein within a hierarchy of interwoven interaction networks of the cell, the organism and the population. A physical theory of proteins therefore needs to unify both aspects, the biophysical and the evolutionary. Specifically, it should provide a model of how the DNA gene is mapped into the functional phenotype of the protein.We review several physical approaches to the protein problem, focusing on a mechanical framework which treats proteins as evolvable condensed matter: Mutations introduce localized perturbations in the gene, which are translated to localized perturbations in the protein matter. A natural tool to examine how mutations shape the phenotype are Green's functions. They map the evolutionary linkage among mutations in the gene (termed epistasis) to cooperative physical interactions among the amino acids in the protein. We discuss how the mechanistic view can be applied to examine basic questions of protein evolution and design.

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Section: Biology As a Challenge To Theoristsmentioning

confidence: 99%

Section: Mechanical Views On Protein Evolutionmentioning

confidence: 99%

Colloquium: Proteins: The physics of amorphous evolving matter

2019

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“…In this work we propose a solution for this discrepancy, by benchmarking DCA in models of protein allostery where a material evolves in silico to achieve an "allosteric" task [23][24][25][26][27][28][29]. We consider recent models incorporating elasticity [24][25][26][27]29], in which long-range co-evolution [26], elongated sectors [26] and long-range epistasis [29] are present and can be interpreted in terms of the propagation of an elastic signal [29]. We focus on materials evolved to optimize cooperative binding over large distances [27], and find four types of epistasis (Synergistic, Sign, Antagonistic, Saturation) that exist over a wide spatial range.…”

Section: Introductionmentioning

confidence: 99%

Direct coupling analysis of epistasis in allosteric materials

et al. 2020

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In allosteric proteins, the binding of a ligand modifies function at a distant active site. Such allosteric pathways can be used as target for drug designs, generating considerable interest in inferring them from sequence alignment data. Currently, different methods lead to conflicting results, in particular on the existence of long-range evolutionary couplings between distant amino-acids mediating allostery. Here we propose a resolution of this conundrum, by studying epistasis and its inference in models where an allosteric material is evolved in silico to perform a mechanical task. We find four types of epistasis (Synergistic, Sign, Antagonistic, Saturation), which can be both short or long-range and have a simple mechanical interpretation. We perform a Direct Coupling Analysis (DCA) and find that DCA predicts well mutation costs but is a rather poor generative model. Strikingly, it can predict short-range epistasis but fails to capture long-range epistasis, in agreement with empirical findings. We propose that such failure is generic when function requires subparts to work in concert. We illustrate this idea with a simple model, which suggests that other methods may be better suited to capture long-range effects.

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“…This result supports that in at least some proteins elasticity -possibly non-linear -is an appropriate language to describe allostery (in contrast to intrinsically disordered proteins that may be considered more as liquids than solids, for which the analysis proposed here would not hold). Very recently, there has been a considerable effort to use insilico evolution [16,17] to study how linear elastic materials can evolve to accomplish an allosteric task [18][19][20][21][22][23][24][25][26]. In general, binding a ligand locally distorts the protein, which is modelled by imposing local displacements at some site, generating an extended elastic response that in turn determines fitness (chosen specifically to accomplish a given task).…”

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confidence: 99%

Mechanics of allostery: contrasting the induced fit and population shift scenarios

Ravasio

Flatt

Yan

et al. 2019

Preprint

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In allosteric proteins, binding a ligand can affect function at a distant location, for example by changing the binding affinity of a substrate at the active site. The induced fit and population shift models, which differ by the assumed number of stable configurations, explain such cooperative binding from a thermodynamic viewpoint. Yet, understanding what mechanical principles constrain these models remains a challenge. Here we provide an empirical study on 34 proteins supporting the idea that allosteric conformational change generally occurs along a soft elastic mode presenting extended regions of high shear. We argue, based on a detailed analysis of how the energy profile along such a mode depends on binding, that in the induced fit scenario there is an optimal stiffness k * a ∼ 1/N for cooperative binding, where N is the number of residues involved in the allosteric response. We find that the population shift scenario is more robust to mutation affecting stiffness, as binding becomes more and more cooperative with stiffness up to the same characteristic value k * a , beyond which cooperativity saturates instead of decaying. We confirm numerically these findings in a non-linear mechanical model. Dynamical considerations suggest that a stiffness of order k * a is favorable in that scenario as well, supporting that for proper function proteins must evolve a functional elastic mode that is softer as their size increases. In consistency with this view, we find a significant anticorrelation between the stiffness of the allosteric response and protein size in our data set.Many proteins are allosteric: binding a ligand at one or several allosteric sites can regulate function at a distant site, a long-range communication often accompanied by large conformational changes [1,2]. There is a considerable interest in predicting the amino acids involved in this communication, or "allosteric pathway", from structure or sequence data [3,4], since they can be used as targets for drug design [5]. Yet, understanding the physical principles underlying such action at a distance in proteins remains a challenge [6,7]. From a thermodynamic standpoint, two distinct views have been proposed. In the induced fit scenario, exemplified by the Koshland-Némethy-Filmer (KNF) model [8], the protein essentially lies in one single state. The latter changes as binding occurs, leading to a conformational change. In an energy landscape picture such as that of Fig.1B, it corresponds to a displacement of the energy minimum upon binding. By contrast, in the population shift model, exemplified by the Monod-Wyman-Changeux (MWC) model [9], two states are always present. Their relative stability can change sign upon binding, leading to an average conformational change. Although each of these models presumably applies to various proteins, they do not specify which designs allow for efficient action at a distance, and how robust these designs are to mutations [10].In several proteins -see below for a systematic study -it has been observed that the allosteri...

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Design of Elastic Networks with Evolutionary Optimized Long-Range Communication as Mechanical Models of Allosteric Proteins

Cited by 56 publications

References 51 publications

Colloquium: Proteins: The physics of amorphous evolving matter

Colloquium: Proteins: The physics of amorphous evolving matter

Direct coupling analysis of epistasis in allosteric materials

Mechanics of allostery: contrasting the induced fit and population shift scenarios

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